Adipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH
Authors: Markus Boesch, Andreas Lindhorst, Rita Feio-Azevedo, Paola Brescia, Alessandra Silvestri, Matthias Lannoo, Ellen Deleus, Joris Jaekers, Halit Topal, Baki Topal, Tessa Ostyn, Marie Wallays, Lena Smets, Lukas Van Melkebeke, Anetta Härtlova, Tania Roskams, Pierre Bedossa, Jef Verbeek, Olivier Govaere, Sven Francque, Alejandro Sifrim, Thierry Voet, Maria Rescigno, Martin Gericke, Hannelie Korf, Schalk van der Merwe
Journal: Journal of Hepatology (2023)

Background & AimsNon-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions, fueled by the obesity pandemic. In NAFLD, monocytes infiltrate visceral adipose tissue that promote local and hepatic inflammation. It however remains unclear what drives inflammation and how the immune landscape in adipose tissue differs across the NAFLD severity spectrum. We aimed to assimilate the adipose tissue macrophage (ATM) heterogeneity in a NAFLD cohort.MethodsVisceral adipose tissue macrophages from lean and obese patients stratified into NAFLD phenotypes underwent single-cell RNA sequencing. Adipose tissue vascular integrity and breaching was assessed on protein level for targets of interest via immunohistochemistry and immunofluorescence.ResultsWe discovered multiple ATM populations, including resident vasculature-associated macrophages (ResVAMs) and distinct metabolically active macrophages (MMacs). Using trajectory analysis, we show that ResVAMs and MMacs replenish from a common transitional macrophage subtype (TransMac) and during NASH, MMacs are not effectively replenished by TransMac precursors. We postulate an accessory role for MMac and ResVAMs in protecting the adipose tissue vascular barrier, since they both interact with endothelial cells and localize around the vasculature. Across the NAFLD severity spectrum however, both these subsets become altered and this coincided with an adipose tissue vasculature breach characterized by albumin extravasation into the perivascular tissue.ConclusionsNAFLD-related macrophage dysfunction coincide with a loss of adipose tissue vascular integrity providing a strong plausible mechanism by which tissue inflammation is perpetuated in adipose tissue and downstream in the liver.Impact and implicationsOur study describe for the first time the myeloid cell landscape in human visceral adipose tissue at single cell level within a cohort of well-characterised NAFLD patients. We report unique NASH-specific transcriptional changes within metabolically active macrophages (MMacs) and resident vasculature-associated macrophages (ResVAM) and we demonstrate their spatial location surrounding the vasculature. These dysfunctional transcriptional macrophage states, coincided with the loss of adipose tissue vascular integrity, providing a strong plausible mechanism by which tissue inflammation is perpetuated in adipose tissue and downstream in the liver. Our study provide a theoretical basis for new therapeutic strategies to be directed towards reinstating ResVAM and MMac endogenous metabolic and homeostatic and cytoprotective mechanisms including their function to protect the vascular integrity and barrier.